DESCRIPTION (Adapted from the application): Filamentous tau inclusions, in addition to extensive neuron loss and gliosis, are the neuropathological hallmark lesions of neurodegenerative tauopathies including Alzheimer disease (AD), Down's syndrome, progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC), Pick's disease, corticobasal degeneration (CBD), frontotemporal dementia (FTDs) and FTD with Parkinsonism linked to chromosome 17 (FTDP-17). The development of tau pathology has long been suspected to represent a final common pathway for nerve cell death but there had been little or no evidence to support this concept until recently when a large number of pathogenic tau gene mutations were identified in more than 20 distinct FTDP-17 kindreds and the applicants showed that some of the mutations cause disease by altering tau gene regulation and others cause tau protein dysfunction. These data provide unequivocal support for the hypothesis that defects in the tau gene alone are sufficient to cause a neurodegenerative disorder. Thus, in project 3, they will test the hypothesis that FTDs and related tauopathies are caused by genetic and epigenetic perturbations that alter the expression, function or biochemistry of tau proteins. To accomplish this, they will identify mutation- specific functional impairments in tau proteins of other FTDP-17 kindreds with new tau gene mutations and determine the mechanisms of tau pathogenesis in sporadic FTDs. They will evaluate whether tau cause neurodegenerative disease by losses of tau function or a gain of toxic function in tau protein. The successful completion of the proposed experiments will provide invaluable insights into the pathogenesis of tau inclusions and their role in neurodegenerative tauopathies, including AD, the most common dementing disorder characterized by prominent tau pathology.